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However, to achieve rapid drug targeting in vivo the ion\u2010pair must be protected against breakdown before the entry into the target tissue. This study aims to investigate if inserting theophylline, when ion\u2010paired to the polyamine transporter substrate spermine, into a cyclodextrin (CD), to form a triplex, could direct the bronchodilator to the lungs selectively after intravenous administration. NMR demonstrates that upon the formation of the triplex spermine protruded from the CD cavity and this results in energy\u2010dependent uptake in A549 cells (1.8\u2010fold enhancement), which persists for more than 20\u00a0min. In vivo, the triplex produces a 2.4\u2010fold and 2.2\u2010fold increase in theophylline in the lungs 20\u00a0min after injection in rats and mice, respectively (<jats:italic>p<\/jats:italic> &lt;\u00a00.05). The lung targeting is selective with no increase in uptake into the brain or the heart where the side\u2010effects of theophylline are treatment\u2010limiting. Selectively doubling the concentration of theophylline in the lungs could improve the benefit\u2010risk ratio of this narrow therapeutic index medicine, which continues to be important in critical care.<\/jats:p>","DOI":"10.1002\/adtp.202000153","type":"journal-article","created":{"date-parts":[[2020,9,25]],"date-time":"2020-09-25T03:57:37Z","timestamp":1601006257000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Cyclodextrin\u2010Stabilized Spermine\u2010Tagged Drug Triplex that Targets Theophylline to the Lungs Selectively in Respiratory Emergency"],"prefix":"10.1002","volume":"3","author":[{"given":"Zarif M.","family":"Sofian","sequence":"first","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences Faculty of Life Sciences &amp; Medicine King's College London  Franklin\u2010Wilkins Building, 150 Stamford Street London SE1 9NH UK"},{"name":"Department of Pharmaceutical Technology Faculty of Pharmacy Universiti Malaya  Kuala Lumpur 50603 Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faiza","family":"Benaouda","sequence":"additional","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences Faculty of Life Sciences &amp; Medicine King's College London  Franklin\u2010Wilkins Building, 150 Stamford Street London SE1 9NH UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie Tzu\u2010Wen","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences Faculty of Life Sciences &amp; Medicine King's College London  Franklin\u2010Wilkins Building, 150 Stamford Street London SE1 9NH UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences Faculty of Life Sciences &amp; Medicine King's College London  Franklin\u2010Wilkins Building, 150 Stamford Street London SE1 9NH UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Barlow","sequence":"additional","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences Faculty of Life Sciences &amp; Medicine King's College London  Franklin\u2010Wilkins Building, 150 Stamford Street London SE1 9NH UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul G.","family":"Royall","sequence":"additional","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences Faculty of Life Sciences &amp; Medicine King's College London  Franklin\u2010Wilkins Building, 150 Stamford Street London SE1 9NH UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doaa B.","family":"Farag","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Misr International University  Cairo 11431 Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khondaker Miraz","family":"Rahman","sequence":"additional","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences Faculty of Life Sciences &amp; Medicine King's College London  Franklin\u2010Wilkins Building, 150 Stamford Street London SE1 9NH UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khuloud T.","family":"Al\u2010Jamal","sequence":"additional","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences Faculty of Life Sciences &amp; Medicine King's College London  Franklin\u2010Wilkins Building, 150 Stamford Street London SE1 9NH UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ben","family":"Forbes","sequence":"additional","affiliation":[{"name":"School of Cancer and Pharmaceutical Sciences Faculty of Life Sciences &amp; 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